HIV-infection causes bone loss that is worsened by antiretroviral therapy (ART) leading to significantly increased fracture rates. As the age demographic of the HIV population is trending rapidly upwards, fears of a looming epidemic of fragility fractures is being raised, as bone loss due to aging and HIV/ART lead to an accelerated loss of bone mass. Little is known about the mechanisms driving bone loss in HIV and ART but the immune system is recognized to potently regulate bone turnover, and as a consequence changes in immune function associated with HIV/ART are likely to impact the skeleton. Although numerous inflammatory cytokines are known to be elevated in HIV-infection/ART and in aging, only RANKL, OPG, and TNF? (a RANKL amplifier) are considered key downstream final effectors of osteoclastogenesis and bone resorption. Virtually all other inflammatory cytokines act by modulating the RANK/RANKL/OPG pathway. B cells are a dominant source of basal OPG, however our preliminary studies show that B-cell OPG is diminished in HIV-infection in humans and animal models in favor of an increase in B-cell RANKL. HIV-infection even when controlled with ART is associated with enduring inflammation that further increases RANKL and TNF?, but OPG remains suppressed. Cumulatively, these events are propitious for enduring bone resorption and loss as reported in clinical studies. Aging too is associated with chronic inflammation and increased RANKL and TNF?, however osteoclastic bone resorption, although elevated, is moderated by a compensatory increase in OPG preventing even more vigorous skeletal destruction. Importantly, our preliminary data suggest that this OPG is derived from B-cells. Because HIV-infection permanently impairs B-cell OPG production, we hypothesize that in the context of chronic HIV-infection there will be a failure in compensatory OPG in aging that is necessary to forestall even greater bone loss. Furthermore, elevated RANKL and TNF? induced by HIV-infection/ART will augment or synergize with the increased RANKL and TNF? associated with aging. These events will conspire to dramatically increase the RANKL/OPG ratio, bone resorption, and bone loss in aged HIV-infected/ART patients. In Specific Aim 1 we will quantify total serum and B-cell and T-cell production of RANKL, OPG and TNF? in uninfected control subjects and in HIV-infected/ART men and women between the ages of 18 and > 60. In Specific Aim 2 we will use a novel animal model of chronic inflammation-induced bone loss that closely replicates the immune perturbations associated with HIV patients on ART to perform detailed mechanistic investigations of the immunoskeletal interface during aging and to test the utility of a novel anti-inflammatory drug to counteract bone loss as a proof of concept for future clinical studies. As the inflammatory state associated with HIV-infection/ART may also underlie other end organ damage that is common in HIV-patients, ameliorating the inflammation state may have significant utility not only for preventing bone loss, but also in ameliorating multiple other pathological states intensified by aging processes.